1. 1 PHOTOFRIN® PDT for High-grade Dysplasia in Barrett’s Esophagus Edvardas Kaminskas, M.D. Medical Officer, CDER, ODE III, DGCDP Milton Fan, Ph.D. Statistical Reviewer, CDER, ODE III, DGCDP CDER GI Drugs Advisory Committee June 26, 2003

2. 2 Overview Background Clinical trials Efficacy endpoints and results Patient disposition Other therapies Safety issues

3. 3 Background HGD is treated to decrease the risk of progression to cancer. Incidence of adenocarcinoma of esophagus increasing; however, –Most cancer cases (94% - 98%) do not have a prior diagnosis of BE –Most BE patients do not develop cancer: annual incidence of 0.5% or less –Cancer risk to an older patient with GERD is very low: 6500 cases per year among 10 million (0.00065 per year)

4. 4 Proposed New Indication “the ablation of high-grade dysplasia (HGD) in Barrett’s esophagus (BE) among patients who are not considered to be candidates for esophagectomy.” “the ablation of HGD in BE among patients who refuse esophagectomy and who are in overall good health.”

5. 5 Clinical Trials in Support of the New Indication PHO BAR 01. Multicenter, randomized, 2-arm trial with minimum 24-month f/u. Patients randomized 2:1 ratio 138 patients to PHOTOFRIN PDT + omeprazole 70 patients to OM (omeprazole) only TCSC 93-07 and TCSC 96-01. Single center, open-label trials, minimum 12-month follow-up. All patients treated with PHOTOFRIN PDT + omeprazole. In 93- 07 patients randomized to 2 light doses; in 96-01, to +/- post-PDT steroids to test effect on stricture incidence. 186 patients, 86 with HGD

6. 6 PHOTOFRIN Photodynamic Therapy in PHO BAR 01 Course 1Course 2Course 3 PatientsN = 130N = 89N = 42 First laser light session Nodule pre-Rx N = 35N = 27N = 12 Balloon light N = 129N = 89N = 41 Second laser light session Treatment of skip areasN = 60N = 49N = 21

7. 7 Efficacy Endpoints Primary endpoint: Complete ablation of HGD and replacement with –normal squamous cell epithelium (CR1), –with some metaplasia remaining (CR2), or –with some low-grade dysplasia or indefinite dysplasia (CR3) at 24 months’ follow-up.

8. 8 Efficacy Endpoints Secondary endpoints: Complete Response (CR3 or better) at 6, 12, 18, and 24 months Quality of Complete Response (% of patients with CR1, CR2, and CR3) Duration of Response Time to Progression to Cancer Time to Treatment Failure (progression to cancer, or other intervening therapy than study treatment) Survival time

9. 9 Efficacy Endpoints Agency’s concerns at Initiation of PHO BAR 01 study: The primary response variable must reflect an improvement in the long-term clinical outcome. Histopathological effects might be a surrogate endpoint for measuring clinical benefit. A follow-up time of 5 years or more recommended, but follow-up of at least 2 to 3 years acceptable.

10. 10 Efficacy Results

11. 11 Efficacy Results

12. 12 Efficacy Results

13. 13 Efficacy Results

14. 14 Efficacy Results PDT group: Patients who progressed to cancer were CR3 responders (6) and non- responders (12). OM Only group: The one (1) responder who progressed to cancer had CR3. The rest (19) were non-responders.

15. 15 Selection of Appropriate Patients Patients without HGD may be referred for PHOTOFRIN PDT. In PHO BAR 01: Patients with HGD referred 485 Diagnosis not confirmed 237 (49%) Diagnosis of HGD should be confirmed by a Reference Laboratory

16. 16 Patient Disposition

17. 17 Other Therapies

18. 18 Safety Issues Acute events related to light treatment (chest pain, abdominal pain, fever, nausea, vomiting, dysphagia, odynophagia) Skin photosensitivity Sub-acute events related to healing –Esophageal strictures, defined as Esophageal narrowing (on endoscopy) that required dilation

19. 19 Safety Issues Strictures

20. 20 Safety Issues Number of Dilations

21. 21 Summary Aggressive surveillance: –Not a good option for most patients in PHO BAR 01 study; 84% chose active treatment. –Information on risk of cancer in HGD is essential for evaluation of treatment options, but may be difficult to obtain. Esophagectomy: –Follow-up information not available.

22. 22 Summary PHOTOFRIN PDT: –Relatively well tolerated. Few withdrew because of adverse events. –No deaths due to treatment or esophageal cancer. –Most SAEs were GI and dehydration. –Strictures were troublesome but manageable.

23. 23 Summary 2-year follow-up suggests PHOTOFRIN PDT is effective. PDT patients had: –50% lower cancer rate –CR rates twice as high. CR associated with lower risk of cancer –Mainly in high quality CR1. Only patients with CR3 progress to cancer

24. 24 Summary But a 2-year follow-up is too short to demonstrate effectiveness in reducing the long-term risk of cancer. Rate of recurrence of HGD not known Rate of HGD progression to cancer not known PHO BAR 02 in process

25. 25

26. 26 Questions for the Committee - 1 Is the proposed INDICATION for PHOTOFRIN PDT appropriate? “the ablation of HGD in BE among patients who refuse esophagectomy and who are in overall good health” If not, what would be an appropriate INDICATION?

27. 27 Questions for the Committee - 2 Is a 2-year follow-up period adequate for the claim of cancer risk reduction in High-grade Dysplasia patients treated with PHOTOFRIN PDT?

28. 28 Questions for the Committee - 3 In view of failure to confirm the diagnosis of High-grade Dysplasia in about 50% of patients, what safeguards would the Committee recommend to insure that only HGD patients are treated with PHOTOFRIN PDT?

29. 29 Questions for the Committee - 4 Should treatment with proton pump inhibitors be recommended, and for what length of time, before treatment of High-grade Dysplasia patients with PHOTOFRIN PDT? Should the diagnosis of High-grade Dysplasia be confirmed by a reference laboratory of acknowledged expertise before PHOTOFRIN PDT is undertaken?

30. 30 Questions for the Committee - 5 Are there ethical concerns about continuing patients in the Omeprazole Only arm of the study?

31. 31 Questions for the Committee - 6 Are there patients with High-grade Dysplasia who should not undergo PHOTOFRIN PDT, because of –safety concerns –uncertainties in the natural history of HGD –other considerations?

32. 32 Questions for the Committee - 7 How would the availability of PHOTOFRIN PDT on the market impact the current approach to the treatment of HGD?